Hyaluronic acid, also referred to as “HA,” is a naturally occurring, water soluble polysaccharide comprising disaccharide units of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc), which are alternately linked, forming a linear polymer. High molecular weight HA may comprise 100 to 10,000 disaccharide units. HA often occurs naturally as the sodium salt, sodium hyaluronate. HA, sodium hyaluronate, and preparations of either HA or sodium hyaluronate are often referred to as “hyaluronan.” As used herein, the terms “HA” and “hyaluronan” also refer to any of the other hyaluronate salts, including, but not limited to, potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate.
HA is a major component of the extra-cellular matrix and is widely distributed in animal tissues. Naturally occurring HA generally has a molecular weight range of about between 6×104 to about 1.2×107 daltons. It has excellent biocompatibility and does not give a foreign body reaction when implanted or injected into a living body. An aqueous solution of hyaluronan is viscous even at relatively low solute concentrations.
Methods of preparing commercially available hyaluronan are well known. Also known are various methods of coupling HA and cross-linking HA to reduce the water solubility and diffusibility of HA, and to increase the viscosity of HA. See, for example, U.S. Pat. Nos. 5,356,883 and 6,013,679, the teachings of which are incorporated herein by reference in their entireties.
Chemically modified HA has been used as a surgical aid to prevent post-operative adhesions of tissues.
Currently there is interest in developing chemically modified HA for delivery of bioactive agents including, for example, therapeutic agents or drugs and biological probes. A major challenge is the development of a delivery vehicle that will provide the appropriate level of bioavailability of a therapeutic agent at the affected area to achieve a desired clinical result. The bioavailability of a drug depends upon the nature of the drug, the drug delivery vehicle used, and the route of delivery, for example, oral, topical, transdermal, mucosal, administration by injection, administration by inhalation, or administration by a combination of two or more of these routes. The bioavailability may be low as a result of, for example, the degradation of the drug by stomach acid, elimination from the gastrointestinal tract, or high aqueous solubility of the drug. As a result, frequent administration may be required, and the amount of drug delivered with each administration may be high, leading to an increase in the occurrence of damaging side effects.
Highly viscous cross-linked HA derivatives are sometimes used as an aid in ophthalmic surgery, such as intraocular lens implantation, glaucoma surgery, vitrectomy, and repair of retinal detachment. However, because of its high viscosity and stability, this cross-linked HA does not readily clear out through the trabecular meshwork, the outlet for aqueous humor egress. Blockage of the trabecular meshwork by the cross-linked HA may contribute to post-operative increases in intraocular pressure, including intraocular spikes (IOPs), the increases in pressure sometimes causing damage to the optic nerve, as well as damage to the cornea.
Cross-linked HA that is highly viscous is also used as a scaffold for tissue engineering in vitro or guided tissue regeneration or augmentation in vivo. Because of the high viscosity and stability of this HA derivative, however, recovery of cells grown on the cross-linked HA can be problematic.